Résumé :
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Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary disease of muscle. Several lines of evidence suggest that FSHD is due to alteration of the expression of FRG1. Transgenic mice overexpressing FRG1P in skeletal muscle were described to develop muscular dystrophy. Even if its precise function is unknown, the FRG1 protein has been reported to be localized to nucleoli, Cajal bodies and speckles. This localization suggests that FRG1 is a component of the spliceosome. Starting from this observation, we hypothesized that the correct generation of the splicing isoforms of FXR1P (Fragile X Related Protein 1) could be altered in FSH patients. FXR1P is one of the homologous proteins of Fragile X Mental Retardation Protein (FMRP), whose absence causes Fragile X Syndrome. Like FMRP, FXR1P is an RNA binding protein involved in several steps of mRNA metabolism, in particular translational control and intracellular localization of a subset of mRNAs (most still unknown). FXR1P plays a vital role during Xenopus and mouse embryogenesis since its complete or partial inactivation has dramatic and muscle-specific effect. Seven distinct FXR1P splicing isoforms have been identified. Four of them are widely expressed in all cell lines and mouse tissues (with the exception of skeletal muscle and heart), whereas the 3 long isoforms are only expressed at high level in skeletal muscle and heart. In agreement with our hypothesis, we observed a reduction of the expression of FXR1P muscle-specific isoforms (mRNA and protein) in cultured myoblasts and myotubes obtained from muscle of FSHD patients. In FSHD myoblasts FXR1P is only localized in the cytoplasm, while in normal cells it appears to be present both in nucleus and in cytoplasm. These results suggest that altered expression/localization of FXR1P may be implicated in the pathogenesis of FSHD and influence the physiopathology of this disease.
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